This page was produced as an assignment for Genetics 677, an undergraduate course at UW - Madison.
Small Molecules: Potential for Cures
Small molecules refer to chemical compounds that interact with proteins. They can have a variety of effects on a protein, including rendering them non-functional or aiding in proper folding (and therefore increasing functionality of an inherently mis-folded, non-functional protein). Finding small molecules that can aid a specific protein can be extremely difficult: even if a researcher were to find a molecule that is shaped well enough to fit a protein (this can be nearly impossible in itself, as proteins have very specific affinities and shapes), but the molecule has to be specific enough not to interfere with other similarly-shaped proteins in the body that are actually functioning properly. However, despite the hardship, small molecules is really where cures are made: pharmaceuticals from antibiotics to HIV inhibitors rely on small molecules to interact with specific proteins or RNA molecules and render them ineffective.
PAH and Small Molecules
Kuvan is a treatment for PKU.
Usually, finding a small molecule that may interact with a specific protein involves the testing and screening of thousands of different proteins in the hopes of finding just one that will work. Computer programs that predict protein structure can sometimes help predict what sort of shape a potential small molecule would need to have in order to be effective. In the case of the PAH protein, small molecules would really only be effective in the case of correcting protein mis-folding. That is, PAH proteins that are nonfunctional due to the disruption in the catalytic site of the protein can't be magically cured through chemicals. Fortunately many cases of PKU are caused by mutations that caused a mis-folded PAH protein, which makes it an eligible candidate for finding chaperone molecules, or molecules that assist in correct folding. Please check out the Literature Review to find out a little about a recent study that found a couple molecules that have potential to help a few specific cases of PAH mis-folding.
The pharmaceutical Kuvan is technically considered a small molecule that can help aid function, though this shouldn't be too surprising as Kuvan is nothing more than a supplement of the co-factor BH4, which occurs naturally. Boosting the amount of BH4 can sometimes help force protein with some residual activity to work faster and/or longer than it usually would [1,2].
The pharmaceutical Kuvan is technically considered a small molecule that can help aid function, though this shouldn't be too surprising as Kuvan is nothing more than a supplement of the co-factor BH4, which occurs naturally. Boosting the amount of BH4 can sometimes help force protein with some residual activity to work faster and/or longer than it usually would [1,2].
References
1. Mitchell JJ, Scriver CR. Phenylalanine Hydroxylase Deficiency. 2000 Jan 10 [updated 2010 May 04]. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-.
2. KUVAN (sapropterin Dihydrochloride) Tablet." Daily Med. NCBI, Dec. 2007. Web. 07 May 2013.
2. KUVAN (sapropterin Dihydrochloride) Tablet." Daily Med. NCBI, Dec. 2007. Web. 07 May 2013.